In Vivo Regulation of Plasma Free Fatty Acids in Insulin Resistance

Abstract Elevated plasma free fatty acid (FFA) concentrations as seen in obesity, insulin resistance, and type 2 diabetes are partly caused by impaired inhibition of intracellular lipolysis in adipose tissue, and this is considered to be part of the insulin resistance syndrome (IRS). Based on predicted insulin resistance at the level of intracellular lipolysis, patients with the IRS would loose weight by disinhibited lipolysis. Since this is not the case in clinical practice, impaired stimulation of intracellular lipolysis must also play a role. We studied acute plasma FFA changes, representing stimulation and inhibition of intracellular adipose tissue lipolysis, in obese patients with IRS and in healthy controls. Thirteen insulin-resistant (IR) subjects (7 men and 6 women) and 10 controls (6 men and 4 women) underwent a mental stress test (20 minutes) preceded by 60 minutes of rest. After mental stress, an oral glucose tolerance test (OGTT) was performed. Baseline FFA levels were higher in IR patients compared to controls (0.59 ± 0.06 and 0.31 ± 0.06 mmol/L, respectively; P = .004). During the 20 minutes of mental stress, FFAs increased significantly in IR subjects from 0.55 ± 0.07 to 0.67 ± 0.07 mmol/L ( P P = .001). Although the absolute change of plasma FFA was not different, the relative increase was lower in IR subjects (28% ± 7%) compared to controls (89 ± 24%; P = .02). Despite the more pronounced mean maximal insulin concentration during the OGTT in IR subjects compared to controls (600.0 ± 126.6 pmol/L and 208.1 ± 30.0 pmol/L, respectively), the relative decrease of FFAs was lower in IR subjects (11% ± 5% v 36% ± 11% in controls after 30 minutes; P = .04). In conclusion, our study shows impaired acute responses of plasma FFAs upon stimulation by mental stress and inhibition by endogenous insulin in insulin resistance in vivo. The presence of both defects helps to understand weight maintenance in insulin resistance.